B This proposal is to study the long term health of 9,240 patients enrolled during 1969-2002 on National Wilms Tumor Study (NWTS) clinical trials and to monitor their offspring for cancer and birth defects. With current therapy, 90% of children with Wilms tumor (WT) will be cured. Survivors, however, are at risk for delayed complications of their disease or treatment that may compromise their quality of life. Therapy for WT has changed over time but still includes surgery, multi-agent chemotherapy and (for some) radiation therapy. The disease typically occurs in early childhood;thus many years of follow-up are required to appreciate its consequences for adult survivors. As the complex genetic and epigenetic events involved in the etiology and pathogenesis of WT are unraveled, we may also discover the mechanisms underlying its long-term sequelae and thus help to develop appropriate preventive strategies. Our specific goals are to determine the incidence, spectrum and risk factors, including disease, treatment and host factors, for selected life- threatening endpoints affecting WT survivors: a) congestive heart failure;b) respiratory failure;c) renal failure;d) second malignant neoplasms;and e) diabetes. We will determine the incidence and causes of late mortality in WT patients and, where possible, compare mortality and chronic disease rates with national population rates. We will study birth rates in WT survivors, pregnancy outcomes and complications, and congenital malformations in their offspring. Heritability and recurrence risks will be estimated through study . of familial disease and follow-up of offspring. We will exploit the unique NWTS resource, including.::-; systematically collected information on birth weights, congenital anomalies, nephrog.enic rests, histologic . type, radiation doses, therapeutic drugs and clinical outcomes, to better characterize, subgroups of patients that may differ with respect to the etiology and pathogenesis of their WT and their susceptibility to long term complications. We will collaborate with molecular biologists by facilitating access to particularly informative patients and by combining the laboratory, clinical, pathology and epidemiologic data for analysis. By elucidating the late complications of WT and its treatment, and by identifying susceptible subgroups, this study will enable future generations of childhood cancer patients and their physicians to select optimum treatments based on knowledge of long term risks as well as short term benefits.